Glioblastoma multiforme (GBM) is the highest grade brain tumor and, unfortunately, has a very poor prognosis. The problem is that the cancer cells invade the surrounding brain tissue, making it impossible to remove or kill all of the tumor cells. Widespread migration also occurs during development of the brain. Neuronal precursor cells express doublecortin (DCX) as they migrate. In fact, DCX is the best marker for migrating precursor cells. Children with mutations of DCX are born with a condition called lissencephaly. These kids have severely stunted brains because their neuronal precursors cannot migrate. We hypothesized that DCX plays a role in the invasiveness of GBMs. To test this hypothesis, we have immunostained 11 GBM's (paraffin blocks) from the UMASS Pathology Department's tumor archive. All of these tumors are strongly positive for DCX. We then stained a series of other brain tumor types and find that DCX expression correlates with invasiveness, consistent with our hypothesis. The goal of this proposal is to determine whether DCX regulates the invasiveness of glioma cells. The Specific Aims are: 1) Determine whether DCX is expressed in human brain tumors. We will use samples from the UMASS Pathology Department to survey human brain tumors for DCX. 2) Test for DCX expression, DCX mutations and DCX subcellular localization in a series of glioma cell lines. 3) Determine the effects of DCX levels on proliferation, motility, and invasiveness. This is a worthy project for several reasons. First, this is an innovative project. Although DCX's role in lissencephaly has received some attention, a role for DCX in cancer is totally new. Second, we have a good team to study this problem. The Ross lab is interested in molecular problems relating to neurobiology and neuro-oncology. Tom Smith is a neuropathologist with many years of experience examining tumors. Phil Zamore, a leader in the RNAi field, is a Collaborator for the project. Scott Litofsky is a neurosurgeon who treats many brain tumor patients, and Chung-Cheng Hsieh is a biostatistician. Third, this is a true R21 proposal. It is exploratory and can be completed in two years. The is potentially a big payoff, namely, identification of DCX's role in glioma cell invasiveness and a new target for development of anti-glioma drugs.